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Ryan Thummel, Shreya Banerjee, Lillian Ranspach, Xixia Luo, Denise Bessert, Joseph Fogerty, Brian D Perkins, Robert Skoff; Vision and myelination defects due to loss of Vps11 function in a zebrafish model of genetic leukoencephalopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6066.
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Genetic Leukoencephalopathies (gLE) are genetic disorders affecting the white matter of the central nervous system. gLEs progressively affect the motor and sensory systems, including the visual system. Our collaborators recently identified a mutation in VPS11 as a causative allele in the gLE phenotypes observed in individuals from Ashkenazi Jewish (AJ) families, with an predicted carrier rate of 1:250 in all AJ individuals. VPS11 functions in a complex of four C-VPS proteins, which are conserved from yeast to humans, and control critical cellular processes in the endolysosomal and autophagy pathways.
We are characterizing a zebrafish vps11 mutant and as a potential model for gLE. Behavioral and optokinetic response (OKR) analysis were used to test visual acuity in zebrafish and immunohistochemical and biochemical approaches were used to give insights into expression and functional defects observed from loss of Vps11.
Behavioral and OKR analysis indicates that vps11 mutant larvae detected light-dark differences but possessed no functional vision. Mutant larvae also showed reduced baseline movement and velocity that correlated with an overall reduction in myelin. Apoptosis of retinal and CNS neurons was also observed. Immunhistochemical and ultrastructural analysis of mutant retinas were suggestive of defects in endolysosomal and autophagy pathways. Finally, we found that Vps11 was highly enriched in mice oligodendrocytes, including the myelin sheath, suggestive of a conserved role for Vps11 in myelin formation in vertebrates.
Our findings support the use of zebrafish to further characterize the vision and motor defects associated with loss of Vps11 function.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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